The long-term goal of this research project is to develop effective strategies for the prevention of prostate cancer progression to androgen independence. Our approach to the effective prevention of prostate cancer progression is the use of combination of physical exercise and low doses of chemopreventive agents. Preliminary studies from our laboratory showed that voluntary exercise inhibited the progression of androgen- dependent LNCaP tumors in severe combined immunodeficient (SCID) mice to androgen independence. We also found that a cholesterol-lowering drug Lipitor (atorvastatin) in combination with the cyclooxygenase-2 (Cox-2) inhibitor Celebrex (celecoxib) more potently inhibited the androgen-independent growth of LNCaP tumors in SCID mice than either agent alone. In addition, treatment of cultured LNCaP cells with serum from exercised mice in combination with low doses of Lipitor and Celebrex resulted in a marked growth inhibition and apoptosis induction. We propose combining voluntary exercise with low doses of Lipitor and Celebrex for prevention of prostate cancer progression. We hypothesize that voluntary exercise will strongly enhance the preventive efficacy of Lipitor and Celebrex on prostate cancer progression to androgen independence by synergistic growth inhibition and apoptosis induction in prostate cancer cells. We also hypothesize that the beneficial influence of voluntary exercise on the preventive efficacy of Lipitor and Celebrex is mediated by modulation of inflammation-related cytokines leading to synergistic inhibition of Akt, Erk1/2 and NF-:B survival pathways. The specific aims are: (1) Determine the preventive efficacy and mechanisms of Lipitor, Celebrex or voluntary exercise alone or in combination on the progression of androgen-dependent LNCaP tumors to androgen independence. (2) In-depth mechanistic studies on the effects of Lipitor, Celebrex, serum from exercised mice and cytokines modulated by exercise on the progression of cultured androgen-dependent LNCaP and CWR22Rv1 cells to androgen independence. Understanding the molecular mechanisms of action for voluntary exercise in combination with Lipitor and Celebrex in prostate carcinogenesis may reveal key molecular targets for future rational design of synergistic combinations of preventive regimens. We anticipate that the anti-carcinogenesis effect of voluntary exercise in combination with Lipitor and Celebrex will have great utility in human cancer prevention.